3-Methoxybenzyl thiourea derivatives and improved lipid compositions containing same

ABSTRACT

1-(3-methoxybenzyl)-3-substituted thiourea antioxidant compounds and improved lipids compositions which are supplemented with amounts of such antioxidant compounds effective for augmenting oxidative stability of the base lipid are provided. Also provided are methods for enhancing the oxidative stability of a lipid comprising supplementing a base lipid in need of enhanced oxidative stability with at least one 1-(3-methoxybenzyl)-3-substituted thiourea compound of the present invention.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation patent application of patentapplication U.S. Ser. No. 09/840,768, filed on Apr. 23, 2001, now U.S.Pat. No. 6,653,505, which is a utility patent application filed from,and claiming the benefit of, prior Provisional Application U.S. Ser. No.60/202,562, filed on May 10, 2000. Application U.S. Ser. No. 09/840,768and Provisional Application U.S. Ser. No. 60/202,562 are each herebyincorporated into this continuation patent application in theirentireties by reference.

FIELD OF THE INVENTION

This invention relates to novel 1-(3-methoxybenzyl)-3-substitutedthiourea compounds and lipid and oil compositions supplemented with suchcompounds having enhanced oxidative stability.

BACKGROUND OF THE INVENTION

Natural lipids and oils are used in pharmaceutical preparations, foodproducts, cosmetics, and various industrial products such as lubricants,coatings, inks, paints, plastics and the like. Such lipids are subjectto oxidative degradation which can affect color, odor, viscosity, andlubricity characteristics thereof, adversely affecting the quality ofthe commercial products containing such lipids. In the food, cosmeticsand pharmaceutical industries, maintaining high quality color and odorof oils and other lipids is important to avoiding oxidation-inducedrancidity which is affected by factors such as the oxygen concentration,light and heat, as well as the degree of unsaturation of the lipid oroil, and the amount of natural or synthetic antioxidants presenttherein. Biodegradable lipids, oils and derivatives thereof used ascutting lubricants are recognized to be adversely affected by heatinduced oxidation.

Meadowfoam (Limnanthes alba) seed oil has been demonstrated to be highlystable to oxidation. Although the identity of the compound(s)responsible for exceptional oxidative stability of meadowfoam oil isheretofore unknown, mixing meadowfoam oil with other oils impartsenhanced oxidative stability to the mixture. (Isbell, T. A., Abbott, T.A. and Carlson, K. D. 1999. Ind. Crops Prod. 9(2):115–123). Severalminor constituents in meadowfoam oil which either diminish oxidativestability or impart small increases in oxidative stability of meadowfoamoil are known, however. (Abbott, T. P. and Isbell, T. A. 1998. Abstractsof the 89th American Oil Chemist's Society Annual Meeting & Expo,Chicago, Ill., May 10–13, 1998. p 66). Refined meadowfoam oil (and otherrefined seed oils and vegetable oils) exhibit reduced oxidativestability as a result of the refining process. Meadowfoam is known tocontain 3-methoxyphenyl actetonitrile, 3-methoxybenzyl isothiocyanateand 3-methoxybenzaldehyde. When added to refined meadowfoam oil atlevels from about 0.1% to 1.0%, these compounds exhibit only small tomoderate antioxidative effects, at best.

Thiourea has been shown to possess antioxidative activity in oils(Kajimoto and Murakami Nippon Eiyo, Shokuryo Gakkaishi 51(4):207–212,1998; Chemical Abstract 129:188538); but thiourea is not very soluble inoils. The oxidative stability of ester-based synthetic lubricants (i.e.,not vegetable oils) stabilized with amine antioxidants has been shown tobe enhanced with specific thioureas (Chao and Kjonaas Amer. Chem. Soc.Preprints, Div. Pet. Chem. 27(2):362–379, 1982). Camenzind and Rolf,Eur. Pat. Appl. EP 91-810474, Chemical Abstract 117:30273, show thatcertain acylated thioureas are able to increase the oxidative stabilityto lubricants and hydraulic fluids.

Mono- and di-substituted thiourea compounds also have been described inU.S. Pat. Nos. 2,154,341, 2,662,096, 3,852,348, and 3,991,008. Migirabet al. Phytochem. 16(11):1719–1721, (1977) disclose methoxy-substitutedaromatic thioureas such as N,N′-bis[(4-methoxyphenyl)methyl]-thiourea(CAS#22313-70-8), which is isolated from P. brazzeana.

There is a need for antioxidant compounds and compositions, especiallynatural antioxidants or derivatives thereof, that are soluble in lipidsand oils and are capable of imparting oxidative stability thereto whenadded at low concentrations.

SUMMARY OF THE INVENTION

We have now unexpectedly discovered that excellent oxidative stabilitymay be imparted to lipids and oils by compounds of the formula I,

wherein R is a C₁–C₂₀ linear or branched alkyl such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, octyl,decyl, nonyl, dodecyl, and the like, C₅–C₇ cycloalkyl, such ascyclopentyl, cyclohexyl or cycloheptyl and the like, C₆–C₇ aryl such asphenyl or benzyl and the like, hydroxy- or alkoxy-substituted C₆–C₇ arylsuch as hydroxyphenyl, methoxyphenyl, ethoxyphenyl, hydroxybenzyl,methoxybenzyl, ethoxybenzyl. Among compounds of the formula I, apresently preferred compound is 1,3-di(3-methoxybenzyl) thiourea, thatis a compound of such formula I where R is a 3-methoxybenzyl moiety. Anamount of a compound of formula I sufficient to impart oxidativestability to a lipid or oil (or compositions containing such lipids oroils) is from about 0.01 wt. % to about 5.0 wt. % based on the totalweight of the lipid or oil.

The present invention also provides oxidatively stable lipidcompositions comprising from about 95 wt. % to about 99.99 wt. % of abase lipid or oil and between about 0.01 wt. % and about 5.0 wt. %, morepreferably between about 0.05 wt. % and 2.0 wt. %, and most preferablybetween about 0.1 wt. % and 1.0 wt. % of a compound of formula I. Lipidsor oils of the present invention containing between about 3 wt. % andabout 5 wt. % or more of a substituted thiourea compound of formula I,based on the total weight of the base lipid or oil composition, may beused as “concentrates” and conveniently added to processed seed oils orother lipids in need of enhanced oxidative stability to provide a lipidor oil composition of the present invention.

The present invention further provides a method for imparting oxidativestability to a base lipid or oil composition in need of enhancedoxidative stability, comprising the step of supplementing a base lipidor oil with an amount of a compound of formula I sufficient to impartenhanced oxidative stability to the base lipid or oil.

Presently preferred compounds of formula I are 1,3-di(3-methoxybenzyl)thiourea; 1-(3-methoxybenzyl)-3-ethyl-2-thiourea;1-(3-methoxybenzyl)-3-propyl-2-thiourea;1-(3-methoxybenzyl)-3-hexyl-2-thiourea;1-(3-methoxybenzyl)-3-dodecyl-2-thiourea;1-(3-methoxybenzyl)-3-(4-hydroxyphenyl)-2-thiourea; and1-(3-methoxybenzyl)-3-(3-methoxyphenyl)-2-thiourea.1,3-di(3-methoxybenzyl) thiourea, which the inventors have identified asa significant natural antioxidant in meadowfoam seed oil, is aparticularly preferred compound of the invention.

It also has been surprisingly found that compounds of formula I, incombination with a benzylamine compound such as N-substitutedbenzylamines, exhibit a synergistic oxidative stabilizing effect inlipids and oils. Various naturally occurring lipids and oils, such asseed oils and vegetable oils contain benzylamine compounds. In thesecases, the synergistic effect may be obtained by supplementing such abase lipid or oil with a compound of formula I and, optionally, with anexogenously added benzylamine compound in an amount sufficient to impartyet a further enhancement in oxidative stability. Thus, another aspectof the present invention entails lipid compositions comprising (i) acompound of Formula I and (ii) a benzylamine or N-substitutedbenzylamine compound to impart enhanced oxidative stability.

DETAILED DESCRIPTION OF THE INVENTION

In one of its aspects, the present invention entails1-(3-methoxybenzyl)-3-substituted thiourea compounds of the formula:

wherein R is selected from the group consisting of C₁–C₂₀ linear orbranched alkyl; C₅–C₇ cycloalkyl; alkoxy-substituted C₅–C₇ cycloalkyl;hydroxy-substituted C₅–C₇ cycloalkyl; C₆–C₇ aryl; hydroxy-substitutedC₆–C₇ aryl; and alkoxy-substituted C₆–C₇ aryl. In a particularlypreferred embodiment, the substituted aryl moiety is a3-hydroxy-substituted or 3-alkoxy-substituted aryl compound.

In another of its aspects, the present invention entails a lipidcomposition with enhanced oxidative stability comprising from about 95wt. % to about 99.99 wt. % of a base lipid and from about 0.01 wt. % toabout 5.0 wt. %, more preferably between about 0.05 wt. % and 2.0 wt. %,and still more preferably about 0.1 wt. % to about 1.0 wt. % of a1-(3-methoxybenzyl)-3-substituted thiourea compound of the formula:

wherein R is selected from the group consisting of C₁–C₂₀ linear orbranched alkyl; C₅–C₇ cycloalkyl; hydroxy- or alkoxy-substituted C₅–C₇cycloalkyl; C₆–C₇ aryl; and hydroxy- or alkoxy-substituted C₆–C₇ aryl.

In a further of its aspects, the present invention entails a method ofenhancing the oxidative stability of a lipid, comprising the step ofcombining a lipid with an oxidative stability-enhancing amount of acompound of the formula I:

wherein R is selected from the group consisting of C₁–C₂₀ linear orbranched alkyl; C₅–C₇ cycloalkyl; hydroxy- or alkoxy-substituted C₅–C₇cycloalkyl; C₆–C₇ aryl; and hydroxy- or alkoxy-substituted C₆–C₇ aryl.

The compounds of the present invention may be added to essentially anylipid in which the compounds of the invention are soluble to augment theoxidative stability of such lipid. The term “lipid” as used hereinincludes vegetable oils, seed oils, triglycerides, waxes oftriglycerides, and phospholipids. Among the lipids that may besupplemented with amounts of the compounds of the present invention toimpart enhanced oxidative stability are vegetable oil, peanut oil, cornoil, cottonseed oil, safflower oil, soybean oil, rapeseed (canola) oil,palm oil, and olive oil, jojoba wax ester, and lecithin. As used herein,the phrase “base lipid”, “base oil” or equivalent phrase means a lipidor oil to which a compound of formula I has not been exogenously added.

As used herein, “C₁–C₂₀ linear or branched alkyl” shall include methyl,ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl,2-methyl-pentyl, 3-methyl-penyl, hexyl, octyl, decyl, dodecyl, and thelike. The term “C₅–C₇ cycloalkyl” shall include cyclopentyl, cyclohexyland cycloheptyl. The term “hydroxy- or alkoxy-substituted C₅–C₇cycloalkyl” shall include cyclopentyl, cyclohexyl and cycloheptylmoieties that are substituted with an hydroxy, methoxy, ethoxy, orpropoxy group or the like. The term “C₆–C₇ aryl” shall include phenyland benzyl. The term “hydroxy- or alkoxy-substituted C₆–C₇ aryl” shallinclude phenyl and benzyl moieties that are substituted with an hydroxy,methoxy, ethoxy, or propoxy group or the like.

By use of the phrase “enhanced oxidative stability”, “augmentedoxidative stability” or an equivalent phrase, it is meant that a lipidcomposition of the invention has an increased ability to inhibitoxidation as measure by the Oxidative Stability Index (OSI) disclosedherein, as compared to the base lipid or oil (i.e., one not supplementedwith an exogenously added compound of formula I). It is presentlypreferred that a lipid or oil composition of the invention exhibit anOSI value at least 10% greater, more preferably at least 100% greater,and most preferably at least about 200% greater or more than the OSIvalue of the base lipid or base oil composition to which it is compared,when the OSI test is carried out at a temperature between about 110° C.and about 130° C.

Compounds of the formula I may be synthesized by reacting3-methoxybenzylamine and an appropriately selected isothiocyanatecompound of the Formula II S═C═N—R, wherein R is defined the same as forcompounds of Formula I. The reaction may be carried out by slowly addingthe isothiocyanate to an aqueous solution of 3-methoxybenzylamine,preferably under a nitrogen atmosphere. The thiourea product of thereaction, which is a compound of formula I, may be recovered andpurified by mixing the reaction products with a solvent that is notmiscible with water but one that is a solvent for the thiourea, such asmethylene chloride, chloroform, toluene or diethyl ether. The waterlayer may or may not be acidified to enhance separation and recovery ofthe thiourea compound of the invention. The thiourea, dissolved in thesolvent layer, can be drawn off from the water layer, dried and theresulting crude thiourea purified by recrystallization in an appropriatesolvent such as ethanol. See, Example 1. See also, generally, theprocedure of Moore and Crossley, Organic Synthesis 2, 617–618 (note 4).

The reactants, 3-methoxybenzylamine and an appropriate isothiocyanatecompound as defined above, may be obtained commercially or synthesizedby routine methods known in the art, and the resultant product compoundsof formula I may be readily isolated by routine methods well-known tothose having ordinary skill in the art. Suitable isothiocyanatereactants for synthesizing compounds of the present invention may beobtained as well-known in the art from degradation of glucosinolatespresent in seed oils and other lipids. In an aqueous solution containingthe enzyme thioglucosidase, glucosinolate compounds are degraded intoisothiocyanates and other degradation products. See, Vaughn, et al., J.Chem. Ecol. 22, 1939–49 (1996); and C. VanEtten and H. Tookey, (1983)Glucosinolates, pp. 15–30 in M. Rechcigl (ed.) “Naturally Occurring FoodToxicants,” CRC Press, Boca Raton, Fla. The isothiocyanate fraction ofthe glucosinolate breakdown products thus may be isolated and reactedwith 3-methoxybenzylamine as described above to provide compounds of thepresent invention. Approximately 100 glucosinolate compounds have beenidentified in plants from 11 different plant families including mustard,rapeseed, cabbage, garlic mustard and crambe (S. F. Vaughn, 1999.Glucosinolates as Natural Pesticides in Biologically Active NaturalProducts: Agrochemicals, H. G. Cutler and S. J. Cutler, Eds, CRC Press,Boca Raton, Fla.) Oils isolated from glucosinolate containing plants arenormally deodorized by steam sparging to remove volatile compounds whichincludes isothiocyanates and amines. Thus, a variety of isothiocyanatecompounds and benzylamine compounds may be obtained from the wastedistillation product generated in the process of purifying such oils andemployed as reactants in synthesizing compounds of the presentinvention.

3-methoxybenzylamine may be purchased commercially or may be isolatedfrom meadowfoam oil by extraction into an immiscible acidified aqueouslayer which is separated from the oil, washed with a nonpolar solvent,treated with a base to lower pH, and the amine extracted into animmiscible solvent. The 3-methoxybenzylamine compound may be furtherpurified by crystallization from ethanol or similar solvent and/orpurified by reverse-phase HPLC using a C18 column, eluting with agradient starting at 100% methanol and proceeding to about 80%methanol:20% chloroform. The peak containing 3-methoxybenzylamine may beidentified by its retention time on the HPLC column in comparison to theretention time for a known standard sample of 3-methoxybenzylamine.Other natural amines may be purchased commercially or may be similarlyextracted from natural sources and purified with reference to knownstandard samples and/or identified by standard chemical methods foridentification of amines (e.g., chromatography, infrared spectroscopy,mass spectroscopy, elemental analysis, nuclear magnetic resonanceanalysis and the like).

The oxidative stability of a lipid, with and without addition of acompound of the present invention, may be determined by procedures thatare described in the literature. See, for example, K. Tian and P.Dasgupta, Anal. Chem. 71, 1692–98 (1999). A presently preferred methodof determining oxidative stability of lipids and oils employs theoxidative stability index (OSI), which determines the oxidativestability of an oil by passing air through a sample under stringenttemperature control. (Firestone, Oxidative Stability Index (OSI):Official Methods of Recommended Practices of the American Oil Chemists'Society, 4^(th) Ed. American Oil Chemists Society, Champaign Ill. Cd126-92.) In this method, a stream of air is passed through the oilsample, which aids in the rapid degradation of the triglyceride intovolatile organic acids. The air stream flushes the volatile acids fromthe oil into a conductivity cell containing water where the acids aresolubilized. These acids, once dissolved in the water solution,disassociate into ions, thus changing the conductivity of the water.Therefore, a continuous measure of the conductivity of the cell bycomputer will indicate when a rapid rise in the conductivity occurs thatcorresponds to the induction point, oxidative failure of the sample. Thetime to the induction point is the OSI time. An AOCS standard method hasbeen recently developed and a collaborative study has also beenpublished (Jebe et al., J. Am. Oil Chem. Soc. 70, 1055–61 (1993)),demonstrating that the OSI method has good reproducibility among samplesand laboratories. Saturated fatty acid methyl ester (FAME) standardscommercially available from Alltech Associates (Deerfield, Ill.) may beused to calibrate the OSI determinations.

OSI determinations may be performed on a oxidative stability instrumentmanufactured by Omnion (Rockland, Mass.) using the AOCS method describedin the above-disclosed Firestone reference. Lipid or oil samples may berun at 110° C. and FAMEs may be tested at 90° C., with air flow set at35 kPa with a resulting velocity of about 140 ml/min. A presentlypreferred method for determining OSI values is described by T. A. Isbellet al., Industrial Crops and Products 9, 115–123 (1999).

Compounds of the formula I may be conventionally mixed with a suitablelipid or oil and solubilized at concentrations up to 3.0%–5.0% or more.It is presently contemplated that concentrations of a compound offormula I between about 0.1% and 1.0% are sufficient to provide up toabout 2-fold to 10-fold enhancement in oxidative stability of a baselipid or oil in need of enhanced oxidative stability. However, lipids oroils of the present invention containing up to 3.0%–5.0% of a compoundof formula I are useful as “concentrates” that can be convenientlydiluted up to 30- to 50-fold or more with a base lipid in need ofenhanced oxidative stability. The base composition of such a concentratemay itself be a lipid or oil such as a seed oil or vegetable oil or afood grade solvent. Moreover, a compound of formula I, optionally incombination with an amine compound, such as 3-methoxybenzylamine, may beprovided in an oil-in-water emulsion or a water-in-oil emulsion, or thelike. The emulsions are presently contemplated to be especially usefulas additives to biodegradable cutting lubricants such as canola oil,soybean oil, vegetable oil estolyte, or other cutting lubricants toenhance the oxidative stability of such lubricants.

In presently preferred embodiments of the lipid or oil compositions ofthe invention, the base lipid or oil is supplemented with an effectiveamount of a compound of formula I, e.g., a concentration of betweenabout 0.1% and 1.0%, as well as a benzylamine compound present in anamount sufficient to augment the oxidative stability imparted by thecompound of formula I. The amount of a benzylamine compound to be addedto a lipid or oil composition of the invention may be determined byobserving increases in OSI values as a function of amount of thebenzylamine compound added. While a base lipid or oil may inherentlycontain an amine compound, additional amounts of an amine compound,preferably 3-methoxybenzylamine, may be added to a lipid or oil that hasbeen supplemented with a compound of formula I to increase the oxidativestability of such a lipid or oil composition of the present invention.The amount of such an amine compound to be added to a lipid or oilcomposition of the invention to achieve a synergistic anti-oxidationeffect may be determined empirically by adding predetermined amounts ofthe amine compound to aliquots of the lipid or oil compositioncontaining a compound of formula I and measuring the increase in OSIvalue obtained.

The following nonlimiting examples further describe the preparation ofthe compounds of the invention. Unless otherwise stated, all percentagesare weight percentages (wt. %).

EXAMPLE 1

This example demonstrates the synthesis of 1,3-di(3-methoxybenzyl)thiourea. To a three neck, 100 ml flask fitted with a condenser, arubber syringe septum and a nitrogen inlet was added 20 ml water and 3.6g (25.8 mmol) of 3-methoxybenzyl amine. The reaction vessel was purgedwith nitrogen and stirred with a teflon-coated magnetic stir bar.3-Methoxybenzyl isothiocyanate 2.59 ml (3.0 g, 16.7 mmol) was addeddropwise (˜1 drop/5–10 s) from a glass syringe. A separate layer formsand the mixture was stirred for 1 h at room temperature. The water layerwas acidified with 1 M HCl (about 10 ml) to pH 5.5. Methylene chloride(15 ml) was added and the two layers transferred to a separator funnel.The lower layer (methylene chloride) was removed. The water layer waswashed with methylene chloride, twice more with 10 ml methylenechloride, and the combined CHCl₂ solutions were washed with 0.1 M HCland then water. The CHCl₂ solution was dried over 3A molecular sievesand then evaporated to dryness in a rotating solvent evaporator. Theresulting viscous liquid was taken up in 20 ml ethanol that had beenheated to 35° C. and the product recrystallized by cooling in arefrigerator twice from ethanol as white crystals, dried in vacuum atroom temperature and weighed. A second recrystallization was made fromthe mother liquor to retrieve additional product for a yield of 79.8% inthe first crystal batch and 83.2% for the combined batches of crystals.Analysis of the product by NMR, mass spectroscopy and elemental analysisrevealed the product to be 1,3-di(3-methoxybenzyl) thiourea.

EXAMPLE 2

Jojoba oil (extracted from jojoba seed with hexane) is a wax ester withmonounsaturated C20 and C22 acids and alcohols esterified together.Jojoba oil (20 g) was mixed with 20 mg (0.1%) of the1,3-di(3-methoxybenzyl) thiourea prepared in Example 1. An OxidativeStability test at 110° C. on 5 g samples of the mixture (in triplicate)revealed an OSI time of 64.2 h, a 30% improvement compared to an OSItime of 49.2 h for the jojoba oil alone. OSI time is the time for oxygenbubbling through the oil at a constant rate to break the oil down andgenerate detectable oxidation products. When the 1,3-di(3-methoxybenzyl)thiourea product from Example 1 was added at the 1% level, OSI timeincreased to 168 h, a 241% improvement as compared to jojoba oil alone.

EXAMPLE 3

Refined meadowfoam oil is a highly monounsaturated vegetable oil whoseoxidative stability is reduced in refining processes. Meadowfoam oil (20g, Lot #C-9773, The Fanning Corp) was mixed with 20 mg (0.1%) of the1,3-di(3-methoxybenzyl) thiourea prepared in Example 1. An OxidativeStability test at 110° C. on 5 g samples of the mixture (in triplicate)revealed an OSI time of 76.4 h, a 15% improvement compared to an OSItime of 66.3 h for the meadowfoam oil alone. When the1,3-di(3-methoxybenzyl) thiourea product from Example 1 was added at the1% level, OSI time increased to 211 h, a 218% improvement.

EXAMPLE 4

The 1,3-di(3-methoxybenzyl) thiourea prepared in Example 1 was mixed at0.1%, 0.5% or 1.0% with refined meadowfoam oil (Lot #CW-4551, TheFanning Corp) and the oxidative stability of the mixtures compared tothat of refined meadowfoam oil at 130° C. The OSI times were 49.8 h, 159h and 172 h respectively for the mixtures containing the thioureacompared to an OSI time of 14.9 h for this lot of refined meadowfoam oilwith no additives at 130° C. Accordingly, supplementing the refinedmeadowfoam oil with 0.1%, 0.5%, and 1.0% 1,3-di-3-methoxybenzyl thioureaprovided increases in the OSI time of 234%, 967%, and 1054%,respectively.

EXAMPLE 5

High oleic sunflower oil is a highly monounsaturated vegetable oil. Higholeic sunflower oil (20 g, Florasun Brand, Floratech, Gilbert, Ariz.)was mixed with 200 mg (1.0%) of the 1,3-di(3-methoxybenzyl) thioureaprepared in Example 1. An Oxidative Stability test at 130° C. on 5 gsamples of the mixture (in triplicate) revealed an OSI time of 157 h, a1720% improvement compared to an OSI time of 9.13 h for the sunfloweroil alone.

EXAMPLE 6

Disubstituted thioureas available commercially that do not have a3-methoxybenzyl moiety have lower antioxidant protection formonounsaturated oils. Thus, 1,3-bis(2-methoxyphenyl)-2-thiourea (AldrichChem Co.) added at 0.1% to refined meadowfoam oil gave an OSI time of37.1 h at 130° C., a 34% lower value than for the thiourea produced inExample 1. Likewise, 1,3-bis(3-methoxyphenyl)-2-thiourea at 0.1% addedto refined meadowfoam oil gave an OSI time of 27.0 h, an 84% lower valuethan for the thiourea produced in Example 1.

EXAMPLE 7

Soybean oil is a highly polyunsaturated vegetable oil. Soybean oil (20g) was mixed with 200 mg (1.0%) of the 1,3-di(3-methoxybenzyl) thioureaprepared in Example 1. An Oxidative Stability test at 130° C. on 5 gsamples of the mixture (in triplicate) revealed an OSI time of 6.4 h, an831% improvement compared to an OSI time of 0.77 h for the soybean oilalone.

EXAMPLE 8

Milkweed seed oil is a highly polyunsaturated vegetable oil. Milkweedseed oil (20 g, extracted from the seed with hexane) was mixed with 200mg (1.0%) of the thiourea prepared in Example 1. An Oxidative Stabilitytest at 130° C. on 5 g samples of the mixture (in triplicate) revealedan OSI time of 2.78 h, an 654% improvement compared to an OSI time of0.42 h for the milkweed oil alone.

EXAMPLE 9

Analysis of crude and refined meadowfoam oil by high performance liquidchromatography (hplc) gave a peak at retention time 9.5 minutes in thecrude but not the refined oil. The retention time for the compoundsynthesized in Example 1, above, was 9.575 to 9.613 in differentconcentrations. Also, an extract of crude meadowfoam oil withacetonitrile solvent was separated into its components by hplc and onecomponent was identified by mass spectroscopy, NMR and elementalanalysis to be 1,3-di(3-methoxybenzyl) urea, an oxidized form of thethiourea synthesized in claim 1. Accordingly, 1,3-di(3-methoxybenzyl)thiourea is shown to be a natural component in crude meadowfoam oil whenextracted from the seed and not refined.

1. A compound of the formula:

wherein R is a C₁–C₂₀ linear or branched alkyl, a C₆–C₇ aryl, ahydroxy-substituted C₆–C₇ aryl or an alkoxy-substituted C₆–C₇ aryl, andwherein the compound enhances the oxidative stability of a lipid or oilto which the compound is added, with the proviso that R is not phenyl,octyl or octadecyl.
 2. A compound of claim 1 wherein R is a C₁–C₂₀linear or branched alkyl.
 3. A compound of claim 1 wherein R is a C₆–C₇aryl, a hydroxy-substituted C₆–C₇ aryl or an alkoxy-substituted C₆–C₇aryl.
 4. A compound of claim 2 wherein R is methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl, pentyl, 2-methyl pentyl,3-methyl pentyl, hexyl, decyl, nonyl or dodecyl.
 5. A compound of claim3 wherein R is benzyl, hydroxyphenyl, hydroxybenzyl, methoxyphenyl,ethoxyphenyl, methoxybenzyl or ethoxybenzyl.
 6. A compound of claim 3wherein R is a 3-hydroxy-substituted or 3-alkoxy-substituted arylmoiety.
 7. A compound of claim 1 wherein the compound is1,3-di(3-methoxybenzyl) thiourea,1-(3-methoxybenzyl)-3-ethyl-2-thiourea,1-(3-methoxybenzyl)-3-propyl-2-thiourea,1-(3-methoxybenzyl)-3-hexyl-2-thiourea,1-(3-methoxybenzyl)-3-dodecyl-2-thiourea,1-(3-methoxybenzyl)-3-(4-hydroxyphenyl)-2-thiourea or1-(3-methoxybenzyl)-3-(3-methoxyphenyl)-2-thiourea.
 8. A compound ofclaim 7 wherein the compound is 1,3-di(3-methoxybenzyl) thiourea.
 9. Acomposition comprising a base lipid or oil supplemented with anoxidative stability-enhancing amount of a compound of the formula:

wherein R is a C₁–C₂₀ linear or branched alkyl, a C₅–C₇ cycloalkyl, analkoxy-substituted C₅–C₇ cycloalkyl, a hydroxy-substituted C₅–C₇cycloalkyl, a C₆–C₇ aryl, a hydroxy-substituted C₆–C₇ aryl or analkoxy-substituted C₆–C₇ aryl, and wherein the composition has a greateroxidative stability than an oxidative stability of the base lipid or oilprior to supplementation with the compound, with the proviso that thecompound is not 1,3-di(3-methoxybenzyl) thiourea.
 10. A composition ofclaim 9 wherein R is a C₁–C₂₀ linear or branched alkyl.
 11. Acomposition of claim 9 wherein R is a C₅–C₇ cycloalkyl, analkoxy-substituted C₅–C₇ cycloalkyl or a hydroxy-substituted C₅–C₇cycloalkyl.
 12. A composition of claim 9 wherein R is a C₆–C₇ aryl, ahydroxy-substituted C₆–C₇ aryl or an alkoxy-substituted C₆–C₇ aryl. 13.A composition of claim 9 wherein the base lipid or oil is supplementedwith from about 0.01 wt. % to about 5.0 wt. % of the compound, based onthe total weight of the base lipid or oil.
 14. A composition of claim 13wherein the base lipid or oil is supplemented with from about 0.05 wt. %to about 2.0 wt. % of the compound.
 15. A composition of claim 14wherein the base lipid or oil is supplemented with from about 0.1 wt. %to about 1.0 wt. % of the compound.
 16. A composition of claim 12wherein the compound is 1-(3-methoxybenzyl)-3-ethyl-2-thiourea,1-(3-methoxybenzyl)-3-propyl-2-thiourea,1-(3-methoxybenzyl)-3-hexyl-2-thiourea,1-(3-methoxybenzyl)-3-dodecyl-2-thiourea,1-(3-methoxybenzyl)-3-(4-hydroxyphenyl)-2-thiourea or1-(3-methoxybenzyl)-3-(3-methoxyphenyl)-2-thiourea.
 17. A composition ofclaim 9 wherein the base lipid or oil is a seed oil or vegetable oil.18. A composition of claim 9 wherein the base lipid or oil is meadowfoamoil, peanut oil, corn oil, cottonseed oil, safflower oil, soybean oil,high oleic sunflower oil, milkweed seed oil, rapeseed oil, palm oil,olive oil, jojoba wax ester, jojoba oil, lecithin or another vegetableoil.
 19. A composition of claim 18 wherein the base lipid or oil isjojoba oil, meadowfoam oil, high oleic sunflower oil, soybean oil ormilkweed seed oil, and wherein the base lipid or oil is supplementedwith from about 0.1 wt. % to about 1.0 wt. % of the compound.
 20. Acomposition of claim 9 wherein the base lipid or oil contains one ormore benzylamine or N-substituted benzylamine compounds.
 21. Acomposition of claim 20 wherein the base lipid or oil is meadowfoam seedoil.
 22. A composition of claim 9 wherein the base lipid or oil is alsosupplemented with an oxidative stability-enhancing amount of one or morebenzylamine or N-substituted benzylamine compounds.
 23. A composition ofclaim 9 wherein the composition exhibits an Oxidative Stability Indexvalue of at least about 10% greater than an Oxidative Stability Indexvalue of the base lipid or oil prior to supplementation with thecompound when an Oxidative Stability Index test is carried out at atemperature between about 110° C. and about 130° C.
 24. A composition ofclaim 23 wherein the composition exhibits an Oxidative Stability Indexvalue of at least about 100% greater than the Oxidative Stability Indexvalue of the base lipid or oil.
 25. A composition of claim 24 whereinthe composition exhibits an Oxidative Stability Index value of at leastabout 200% greater than the Oxidative Stability Index value of the baselipid or oil.
 26. A composition of claim 25 wherein the compositionexhibits an Oxidative Stability Index value of at least about 500%greater than the Oxidative Stability Index value of the base lipid oroil.
 27. A composition of claim 26 wherein the composition exhibits anOxidative Stability Index value of at least about 800% greater than theOxidative Stability Index value of the base lipid or oil.
 28. Acomposition of claim 27 wherein the composition exhibits an OxidativeStability Index value of at least about 1,000% greater than theOxidative Stability Index value of the base lipid or oil.
 29. Acomposition of claim 28 wherein the composition exhibits an OxidativeStability Index value of at least about 1,500% greater than theOxidative Stability Index value of the base lipid or oil.
 30. A methodfor enhancing the oxidative stability of a base lipid or oil comprisingthe step of combining the base lipid or oil with an oxidativestability-enhancing amount of compound of the formula:

wherein R is a C₁–C₂₀ linear or branched alkyl, a C₅–C₇ cycloalkyl, analkoxy-substituted C₅–C₇ cycloalkyl, a hydroxy-substituted C₅–C₇cycloalkyl, a C₆–C₇ aryl, a hydroxy-substituted C₆–C₇ aryl or analkoxy-substituted C₆–C₇ aryl.
 31. A method of claim 30 wherein the baselipid or oil is combined with from about 0.05 wt. % to about 2.0 wt. %of the compound.
 32. A method of claim 31 wherein the compound is1,3-di(3-methoxybenzyl) thiourea,1-(3-methoxybenzyl)-3-ethyl-2-thiourea,1-(3-methoxybenzyl)-3-propyl-2-thiourea,1-(3-methoxybenzyl)-3-hexyl-2-thiourea,1-(3-methoxybenzyl)-3-dodecyl-2-thiourea,1-(3-methoxybenzyl)-3-(4-hydroxyphenyl)-2-thiourea or1-(3-methoxybenzyl)-3-(3-methoxyphenyl)-2-thiourea.
 33. A method ofclaim 32 wherein the compound is 1,3-di(3-methoxybenzyl) thiourea.
 34. Acompound of claim 1 with the additional proviso that R is notmethoxybenzyl or methyl.
 35. A compound of claim 3 wherein R is a C₆–C₇aryl or a hydroxy-substituted C₆–C₇ aryl.
 36. A compound of claim 4wherein R is ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,pentyl, 2-methyl pentyl, 3-methyl pentyl, hexyl, decyl, nonyl ordodecyl.
 37. A compound of claim 5 wherein R is benzyl, hydroxyphenyl,hydroxybenzyl, methoxyphenyl, ethoxyphenyl or ethoxybenzyl.
 38. Acompound of claim 7 wherein the compound1-(3-methoxybenzyl)-3-ethyl-2-thiourea,1-(3-methoxybenzyl)-3-propyl-2-thiourea,1-(3-methoxybenzyl)-3-hexyl-2-thiourea,1-(3-methoxybenzyl)-3-dodecyl-2-thiourea,1-(3-methoxybenzyl)-3-(4-hydroxyphenyl)-2-thiourea or1-(3-methoxybenzyl)-3-(3-methoxyphenyl)-2-thiourea.